By Gary Evans

The Secretary’s Advisory Committee on Human Research Protections (SACHRP) recently approved guidelines on paying research participants, addressing a range of issues from “token” payments to frank coercion.

“The idea behind this was to really amplify some of the existing guidance because we know that IRBs have a wide variety of perspectives on what kind of payments are appropriate for subjects. One of the concerns is whether paying subjects to participate in clinical trials is unduly influential,” said SACHRP member Nancy King, JD, who outlined the draft guidelines before the panel at a July 30-31 meeting.

After considerable discussion into the ethical implications of paying subjects too much or too little, SACHRP approved the guidelines, entitled “Addressing Ethical Concerns Regarding Offers of Payment to Research Participants.” The guidelines had not been published as this report was filed.

The background cited in the draft is that in January 2018, the FDA updated its Information Sheet1 regarding payments to participants. Part of this was to clarify that the FDA does not consider reimbursement for travel and lodging at a research site to be an “undue influence” on the decision to participate.

“Other than reimbursement for reasonable travel and lodging expenses, IRBs should be sensitive to whether other aspects of proposed payment for participation could present an undue influence, thus interfering with the potential subjects’ ability to give voluntary informed consent,” the SACHRP guidelines stated. “[The committee] has been asked to consider whether there is a need for additional updates to guidance related to payments that go beyond reimbursement of participant expenses.”

The Office for Human Research Protections defines undue influence as potentially occurring “through an offer of an excessive or inappropriate reward or other overture in order to obtain compliance,” in the guidelines.

“Because influence is contextual and undue influence is likely to depend on an individual’s situation, it is often difficult for IRBs to draw a bright line delimiting undue influence,” SACHRP stated in the guidance. “Although undue influence and coercion are often discussed together, this document focuses primarily on undue influence because genuine offers of payment do not satisfy the definition of coercion.”

SACHRP also focused on payment to “decisionally capable adults” offered in IRB-approved research at all risk levels, including research with and without potential direct benefit to participants. The guidelines try to provide IRBs “with a few more tools” to help determine when payment is appropriate and when it may be unduly influential, King said. It is in avoiding the latter that IRBs may think “it is better to be safe than sorry” and minimize or prohibit payments.

“Our approach is that this is kind of like killing a fly with a sledgehammer,” King said. Instead, SACHRP seeks to break down the types of patients and offer insight on those that raise concerns about undue influence and those that clearly should be permitted.

Coercion was defined for the purposes of ruling it out of the discussion, as it implies pressures that would be inappropriate in a human research concept, King explained. “Coercion entails a threat to violate someone’s rights or fail to fulfill an obligation to him or her in order to obtain compliance by creating a circumstance in which the person has no reasonable alternative but to comply,” the guidelines stated.

Elaborating on this point, King said “coercion is a different concept and doesn’t really apply in the payment situation because generally speaking, offers aren’t coercive, but they may be unduly influential.”

As defined as a “jumping-off point” in the guidelines, undue influence generally entails an “excessive offer … that leads to poor judgment or a compromised decision-making process.” The resulting decision could lead to participant harm, but undue influence raises ethical questions even if no harm is likely to result.

“IRB approval of research should play an important role in minimizing the likelihood of adverse outcomes and promoting effective consent processes,” the guidelines stated. “Thus, SACHRP takes the position that payment raises concerns about undue influence when it appears likely to inhibit potential participants’ adequate consideration of and reflection about important study features, such as risk, burdens, and discomforts, and impair their understanding of the research and their participation in it.”

“What we’re focusing on is whether the amount of payment seems to be such that it impedes participants’ ability to make good decisions about their participation,” King said.

Five SACHRP Recommendations

The committee guideline addressed these issues in five recommendations, beginning with agreement that reimbursement payments do not raise concern about undue influence:

Recommendation 1: SACHRP agrees with and recommends that OHRP adopt the stance on reimbursement payments described in the 2018 FDA information sheet “Payment and Reimbursement to Research Subjects.”

“For example, you go someplace to participate in a study and they pay for your parking,” King said. “Well, that shouldn’t raise concerns.”

The SACHRP guidelines recommend a broad interpretation of reimbursable costs, although noting that lost wages are probably better viewed as a matter for compensation.

The panel defined “compensation” as payment for the participant’s contribution of time and acceptance of research-related burdens and inconvenience, as distinguished from the out-of-pocket costs addressed through reimbursement.

Recommendation 2: SACHRP recommends that OHRP and FDA clarify that compensating participants for their time and effort is not an undue influence.

“Some individuals may have to forgo other sources of income as a consequence of spending time in research,” the guidelines stated. “Compensation at least makes up for some of the financial difference between research participation and other activities. Thus, in these cases, there is no reasons to be concerned that compensation payment would compromise decision-making,” according to the guidelines.

Although compensating participants for time and effort does not necessarily raise concerns about undue influence, it does spur a few immediate questions, King said. “The question then arises: How do you determine what counts as fair compensation?” she said. “Is it an hourly wage? Is it proportionate to the income of the person participating?”

King favored the analogy of jury duty, while saying perhaps research compensation should be somewhat more than typically paid for that civic duty. “The idea is that a modest compensation, which the IRB can calculate in appropriate ways, should not actually raise concerns about undue influence,” she said.

Recommendation 3: SACHRP recommends that OHRP and FDA acknowledge that appreciation payments to research participants do not raise concerns about undue influence.

“A category that I particularly think is important is ‘appreciation’ payments because many who participate in research studies are hospitalized or undergoing treatment at the same time, and reimbursement and compensation are not needs for them,” King said. “[Appreciation] payment is an acknowledgement of the contribution subjects are actually making. It makes sense to regard payments of appreciation, which are usually rather small, as not raising concerns [of undue influence].”

Recommendation 4: SACHRP recommends that OHRP and FDA clarify that incentive payments may raise concerns regarding undue influence in some cases.

“Incentive payments go beyond what participants may be owed as a matter of fairness,” King said. “They are designed very often to ensure rapid and adequate enrollment into a trial and may raise concerns.”

To illustrate this point, the SACHRP guidelines included two different prospective participant scenarios:

Prospective participant 1, whose reasoning about enrolling in an IRB-approved study goes as follows: “If the payment were not so high I probably wouldn’t do this. I’ve thought carefully about the risks and benefits, asked questions about them, and understand … Still, the risks worry me. But I need the money, so I’m going to say yes.”

The SACHRP guidelines concluded, “This participant has been influenced by payment, but not unduly influenced because she has not been asked to join an unreasonable study (assuming adequate IRB review) and because she is making an informed, understanding, and voluntary choice under the circumstances. Her conclusion that study participation is her best available alternative to make money does not make it involuntary.”

In contrast, prospective participant 2 sees the same study and reasons, “I am desperate for money, I don’t care about the risks. I don’t even want to know what they are, just sign me up so I can get paid.”

Participant 2 has been unduly influenced by the offer of payment, the guidelines noted. “He, too, would be enrolling in a reasonable study, but payment has inhibited his adequate consideration of reasons for or against participation.”

Participant 2 “is someone who has not spent enough time making what the IRB, or any of us, would consider a thoughtful decision about participation,” King said.

The guidelines underscored this point, emphasizing that IRBs and investigators have an ethical and regulatory duty to support and encourage rational decisions by possible participants.

“Although individuals are free to make ‘rash’ or ‘snap’ decisions outside the research setting (for example, when accepting a job offer or making a purchase), IRBs and investigators must fulfill their responsibilities for rash participant protection, including assurance of adequate informed consent,” the guidelines stated. IRBs can meet this duty through the overall process of evaluating the incentives, the thoroughness of the consent form, and the circumstances under which consent was given.

“IRBs need not monitor the enrollment process of each individual participant or account for their unique characteristics,” the guidelines stated.

IRBs should not overreact to incentive concerns and simply cut or cancel payments, King warned. “What we would hope to do is ensure that these kinds of participants are provided with opportunities to be more thoughtful about participation,” she said. “Simply saying ‘let’s lower the amount of payment’ raises a certain set of practical and theoretical problems. It may make enrollment difficult. It may actually ensure that the only people who enroll are people for whom any amount of money is important, and that kind of seems unfair.”

Recommendation 5: SACHRP recommends that OHRP and FDA acknowledge that concerns about incentive payments that may be unduly influential can be managed without necessarily lowering or eliminating them, and provide guidance regarding how to minimize the possibility of undue influence.

To avoid these pitfalls, IRBs should encourage investigators to adopt approaches that will support high-quality decision-making. “Make sure it’s a process using teach-back comprehension methods to encourage potential subjects to think and reflect on aspects of the study,” King said. “Incorporate waiting periods and other kinds of support for those people who say, ‘I just don’t have a choice. I need the money.’”

According to the SACHRP guidelines, these approaches include:

  • Setting aside sufficient time for knowledgeable study staff to review the entire consent form with potential participants and answer any questions, rather than permitting a passive consent process in which potential participants are expected to review materials on their own;
  • Including tests of comprehension or teach-back methods could provide an indication that potential participants are aware of and understand key information about the study;
  • Incorporating a waiting period for potential participants to reflect on their desire to participate and potentially discuss the study with trusted others;
  • Considerations that prospective participants’ current interest may conflict with their future interest (for example, asking for reflection of the value to the individual of trading payment for risk that may materialize into harms later).

Overall, the SACHRP committee called for more guidance from the FDA and OHRP on participant payment issues, reiterating concerns that IRBs need help managing undue influence and incentive payments without resorting to King’s “sledgehammer.”

“There are additional considerations, such as timing of payment, that are important,” King said. “We know if you say ‘you will get all your money at the end of the study’ that could encourage people to stay in a study past the point they consider to be safe for themselves.”

SACHRP recommends prorated payments, noting that a study completion bonus could be appropriate.

In a flurry of last-minute wordsmithing, there was an effort to remove the term “token” payments in favor of “appreciation” or other less-loaded adjectives.

“They’re generally minimal, but we called them ‘token’ payments to begin with at early points and I don’t like that. I think it’s dismissive,” said Stephen Rosenfeld, MD, MBA, chairman of SACHRP.

(Editor’s note: Video of the July 30-31 SACHRP meetings can be viewed online at: https://bit.ly/2kFFB7O.)

REFERENCE

  1. U.S. Food & Drug Administration. Information Sheet. Payment and reimbursement to research subjects: Guidance for institutional review boards and clinical investigators, January 2018. Available at: https://bit.ly/2m1BnYo. Accessed Sept. 11, 2019.